This to a system and method of achieving both convective and diffusive transport of plasma across a membrane accompanied by the selective removal of plasma components using sorbents, immobilized enzymes or antibodies followed by reinfusion of the purified plasma to a patient in an extracorporeal blood circulation system without using any plasma pump or transmembrane pressure controls.
Conventional therapeutic processes for the purification of blood extracorporeally include hemodialysis, ultrafiltration, plasmapheresis, hemoperfusion, plasma perfusion and combinations of these, i.e. hemofiltration, plasma exchange, hemodiafiltration and hemodialysis with sorbent regeneration of dialysate. Except for hemoperfusion, where blood is perfused through a column of selective sorbents directly (excepting those sorbents which are encapsulated by a membrane), all of the processes include a semipermeable membrane as an interface between the blood phase and the purification medium.
An electrolyte solution (dialysate solution) serves as the purification medium in hemodialysis. Ultrafiltration and plasmapheresis techniques do not utilize a purification medium. Rather, purification is done by removing a portion of fluid components from the blood plasma by filtration using transmembrane pressure difference as the driving force. Hemodialysis, ultrafiltration and plasmapheresis do not selectively remove specified components. Instead all components below the pore size of the membrane filter are removed by them. Hemodialysis and ultrafiltration use small pore size membranes which are below the size of plasma proteins (i.e. albumin has a mole weight of about 60,000 Daltons). On the other hand, plasmapheresis uses membranes with pore sizes greater than the size of plasma proteins so that large plasma components such as autoantibodies, immune complexes and viruses can be removed from the blood plasma. A distinct disadvantage in this process is that useful plasma components, such as certain proteins, enzymes and hormones, are also removed and lost.
In hemoperfusion and plasma perfusion techniques, selectivity is achieved by using selective sorbents for the binding of components to be removed from the blood. In plasma perfusion, plasma must first be separated from the blood by pumping blood through a membrane plasma filter or, in the alternative, a centrifuge is used to separate plasma from the blood. The plasma obtained as the filtrate or by decanting from the packed cells, is then pumped through a column of sorbents where the plasma is selectively depleted of components bound by the sorbents. The purified plasma is then combined with the filtered or precipitated blood cells and reinfused to the patient.
There are various prior art publications illustrative of the above methods or techniques. Shown in Ohnishi et al., U.S. Pat. No. 4,696,670 (1987) is a method where plasma is separated from blood. The plasma is perfused through a column of immobilized enzymes for the removal of low density lipoproteins (LDL). A complex switching method is used to implement the operation. Larson et al., U.S. Pat, No. 4,361,484 (1982) shows a method where an enzyme, antibody or protein A is immobilized in the pores of a membrane facing away from the blood phase by a chemical binding method. Using an oscillating pressure technique, plasma, or fluid is forced into and out of the membrane to achieve a high degree of convective mass transport. In Marconi et al., U.S. Pat. No. 4,248,704 (1981) a method is shown wherein an enzyme is trapped in a hollow fiber membrane to remove phenylalanine from the blood. This enzyme is impermeable to the membrane; however, phenylalanine permeates through the membrane where it is hydrolyzed by the enzyme.
Langer et al., U.S. Pat. No. 4,373,023 (1983) shows the use of immobilized heparinase on a support such as Sepharose, polyacrylamide or polyHEMA to degrade heparin in blood in an extracorporeal device prior to recirculating the blood to the patient. In this device the plasma is not separated and whole blood is brought into direct contact with the sorbent material.
Grossman, U.S. Pat. No. 3,742,946 (1973) shows a system for the treatment of renal failure which requires removal of the body's excess fluid and metabolic wastes. This system uses a semipermeable tubular membrane through which blood flows. The tubular membrane is surrounded by a closed shell containing a mixture of sorbents. One of the sorbents includes a desiccant which is stated to accelerate the convective transport of water across the membrane. This water gets absorbed and retained by the desiccant present in the shell. It is a objective of the Grossman procedure to retain this water in the shell chamber and not to reinfuse it to the patient. Water transport across the membrane in Grossman's procedure is by diffusion only.
A different system is shown by Skurkovich, U.S. Pat. No. 4,362,155 (1982). This system purifies blood or plasma in three steps which requires three subsystems, i.e. separation of plasma from blood using a plasma separator (filter), purification of the filtered plasma by pumping it through a mixture of sorbents contained in a packed column and reinfusion of the purified plasma to the patient by combining it with the filtered blood and reinfusion of the whole blood. This system is primarily for the removal of interferon and autoantibodies from whole blood or plasma. Nose' et al., U.S. Pat. No. 4,381,775 (1983) and Bensinger, U.S. Pat. No. 4,614,513 (1986) show processes similar to Skurkovich. Bensinger utilizes immobilized protein A sorbent for the removal of autoantibodies and immunoreactive agents from plasma.
Bernstein et al., U.S. Pat. No. 4,863,611 (1989) is directed to the removal of heparin from blood in an extracorporeal blood circulation system. In this system whole blood is in direct contact with a sorbent which may lead to problems such as thrombocytopenia, cellular damage, sorbent fine particle embolization, complement activation and the like. In this system blood is fluidized or recirculated at very high flow rates which leads to blood damage and particle fragmentation. A microemboli filter is required to catch these fine particles. Heparin removal by an immobilized heparinase enzyme sorbent is only about 20-60% of blood flow rate.